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1、艾滋病抗病毒治疗,HIV感染的自然史 抗病毒治疗药物 药品及作用机理 治疗目的 抗病毒治疗前准备 治疗时机、方案 治疗效果 依从性 耐药,ART ARV HAART NNRTI NRTI PI Adherence IRIS DR,临床表现(HIV感染的自然史),急性期 无症状期(临床潜伏期) 临床期(艾滋病期),急性HIV感染期,50%-70%以上的患者在感染后2周到2个月出现。 主要表现为传染性单核细胞增多症样表现 通常在2-4周内自行缓解。,无症状期(临床潜伏期),5%-15%的无症状期患者在2-3年发展为艾滋病称快速进展者。 5%的无症状期患者可以维持正常免疫12年以上称长期存活者。 一
2、般6-10年。,AIDS期,此期具有以下基本特点 体质性疾病 严重的细胞免疫缺陷 发生各种病原感染、多脏器多系统的性机会性感染 发生各种机会性肿瘤,诊断标准(艾滋病期), 原因不明的38以上持续不规则发热,1个月; 慢性腹泻次数多于3次/日,1个月; 6个月之内体重下降10以上; 反复发作的口腔白念珠菌感染; 反复发作的单纯疱疹病毒感染或带状疱疹病毒感染; 肺孢子虫肺炎; 反复发生的细菌性肺炎; 活动性结核或非结核分枝杆菌病;,诊断标准, 深部真菌感染; 中枢神经系统占位性病变; 中青年人出现痴呆; 活动性巨细胞病毒感染; 弓形虫脑病; 青霉菌感染; 反复发生的败血症; 皮肤黏膜或内脏的卡波氏
3、肉瘤、淋巴瘤。 (17)CD4小于200/l,HIV/AIDS实验室诊断,诊断性检测,初筛实验:IFA、ELISA:1985 确认实验:Western blot,预后判定性检测,T细胞亚群检测:流式细胞仪技术 HIV RNA检测,HIV耐药检测,表型耐药:细胞培养技术 基因型耐药:序列测定,杂交技术,RT,Provirus,Proteins,RNA,DNA,RNA,DNA,DNA,RT,Viral protease,Reverse transcriptase,RNA,RNA,DNA,DNA,DNA,(Fusion and entry),HIV Life Cycle,RT,Provirus,Pr
4、oteins,RNA,RNA,RT,Viral maturation,Reverse transcriptase,RNA,RNA,DNA,DNA,DNA,Current antiretroviral targets and agents,ZDV, ddI, ddC, d4T, 3TC, ABC, TDF, FTCDLV, NVP, EFV, TMC125, R278,SQV RTV IDV NFV APV LPV FOS ATZ TPV TMC114 BCV PL-100,Fusion,Integration,Viral protease,PA-457,MK-0518 GS-9137,T-20
5、 TRI-1144,Entry inhibitors,Maraviroc Vicriviroc TNX-355,Timeline of ARV Development,AIDS 1st reported,Eliza,WB, blood screening program,ZDV,ddI,ddC,d4T,3TC, SAQ,RTV, IDV, NVP,NFV, DLV, COM, SAQ-gc,EFV, ABC,APV,Viral load Amplicor 1.0,1981,1984,1994,1992,1991,1985,1987,1995,1996,1997,1999,1998,2000,2
6、001,2002,2003,2005,HIV isolated,Resistance Testing TruGene,Amplicor 1.5,NEJM, Pallela et al.,LPV/r, ddI-EC, TZV,TDF,EFV-600, 3TC-300,ENF NFV-625 ATV FTC FPV,EPV-ABC TDF-FTC TPV,Current Antiretroviral Medications,NRTI Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudi
7、ne ZDV Tenofovir TDFNNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP,PI Amprenavir APV Atazanavir ATV Darunavir DRV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV hard gel HGC tablet INV Tipranavir TPVFusion Inhibitor Enfuvirtide T-20,目前我国所有的抗病毒药物,核苷类:DDI
8、,D4T,3TC,AZT,ABC ,(TDF ?) 非核苷类:EFV ,NVP 蛋白酶:IDV,ATV ,LPV/RTV,New Antiretrovirals in Development,NRTIs/NtRTIs Amdoxovir (DAPD) Apricitabine (AVX754) Compound X Dexelvucitabine (D-d4FC) Racivir ( FTC) SN1212 Protease inhibitors Brecanavir (GW640385) Darunavir (TMC114) P-1946,Entry inhibitors BMS-48804
9、3 Maraviroc NB-2, NB-64 PRO140 TNX-355 Vicriviroc KRH-3955 KRH-3140 TRI-999 TRI-1144,NNRTIs BILR 355 BS CSIC DAPY/DATA Etravirine (TMC125) TMC120 (microbicide) TMC278 UC781 Integrase inhibitors GS-9137 MK-0518 Maturation inhibitors PA-457,J. Gallant CCO 2005,AIDS-related Mortality in the USA,1995 19
10、96 1997 1998 1999 2000 2001,Year,Deaths per 100 person-years,Therapy with a PI (% of patient-days),Deaths,Use of PIs,Palella et al. 8th CROI, 2001,40 35 30 25 20 15 10 5 0,100 75 50 25 0,Impact of Protease Inhibitors on AIDS Mortality,Palella F. et al., New Engl J Med 1998; 338:853-860,HAART Impacte
11、d on AIDS progression and/or death in Hong Kong,Wong et al CID 2004,N=303,N=278,1984-1996,1997-mid 2003,HAART era,Pre-HAART,抗逆转录病毒治疗的目的,抑制病毒的复制病毒载量最大程度的下降 免疫重建 防止耐药的出现存活 疾病进展 传染性,Goals of Therapy & Tools to Achieve Goals,Improvement of quality of life Reduction of HIV-related morbidity and mortality
12、 Restoration and/or preservation of immunologic function Maximal and durable suppression of viral load,Selection of ARV regimen Preservation of future treatment options Rational sequencing of therapy Maximizing adherence Use of resistance testing in selected clinical settings,推迟治疗的潜在益处 避免药物治疗带来的对于生活
13、质量的负面影响及药物毒副反应。 保留治疗选择 推迟药物耐药的发生 患者有更多时间充分理解治疗需求 减少总的服药时间 有机会等待效力更强、毒副反应更少的药物及更好药物组合的出现推迟治疗的潜在风险 由于没有及时接受治疗对免疫系统造成不可逆转的损害 增加进展为艾滋病的可能性 由于没有接受治疗,增加了传播HIV的危险,Initial Treatment: Preferred Components,*Avoid in pregnant women and women with significant pregnancy potential. *Emtricitabine can be used in p
14、lace of lamivudine and vice versa.,OR,NNRTI Option,PI Options,Tenofovir + emtricitabine*Zidovudine + lamivudine*,+,NRTI Options,Initial Treatment: Alternative Components,*Nevirapine should not be initiated in women with CD4 counts 250 cells/mm3 or men with CD4 counts 400 cells/mm3 *Atazanavir must b
15、e boosted with ritonavir if used in combination with tenofovir,OR,NNRTI Option,PI Options,Abacavir + lamivudineDidanosine + (emtricitabine or lamivudine),NRTI Options,Initial Treatment: Other Possible Options,Rationale,ARV drugs or regimens,These are considered acceptable but inferior to preferred or alternative components. They may be used in special circumstances.,Antiretroviral Components in Initial Therapy: NNRTIs,ADVANTAGES Less dyslipidemia and fat maldistribution than in PI-based regimens PI options preserved for future use,